Descrizione del progetto
Decodificare la O-glicosilazione per ottenere nuove conoscenze sulle malattie
La O-glicosilazione, una complessa modificazione post-traduzionale dei carboidrati della superficie cellulare, è legata a una serie di malattie, tra cui malattie infiammatorie intestinali, fibrosi cistica e cancro. Nonostante la sua importanza, i meccanismi alla base della O-glicosilazione e l’impatto sulle malattie sono ancora poco conosciuti. Il progetto GLYCO TOOLS, finanziato dal Consiglio europeo della ricerca, intende comprendere meglio il ruolo della O-glicosilazione, con l’obiettivo di individuare trattamenti e diagnosi efficaci. Il progetto utilizzerà la chimica organica e inorganica di sintesi, l’enzimologia e la glicobiologia per studiare i parametri che controllano la diversità combinatoria degli O-glicani e le relative implicazioni sul legame con i recettori e la segnalazione intracellulare. Questa ricerca innovativa aprirà la strada allo sviluppo di strumenti diagnostici e terapie basati sui glicani.
Obiettivo
Cell surface carbohydrates play key roles in cell recognition mechanisms. O-glycosylation is a ubiquitous post-translational modification that is highly dynamic and responsive to cellular stimuli through the action of cycling enzymes. Expression of specific O-glycans is linked to changes in gene expression in, for example, inflammatory bowel disease, cystic fibrosis and several types of cancer.
Protein-carbohydrate interactions typically exhibit high specificity and weak affinities toward their carbohydrate ligand. This low affinity is compensated in nature by the architecture of the protein, the host presenting the carbohydrate ligands in a multivalent manner or as clusters on the cell or mucosal surface. This effect is known as the multivalency or “cluster–glycoside effect” and has been well documented for lectin–carbohydrate interactions as increasing ligand affinity and selectivity. The fundamental understanding of these glycosylation patterns at molecular and functional levels will allow mechanisms associated with bacterial-host interactions, bowel disease and several cancers to be defined, which will facilitate the identification of effective treatments and diagnostics for these conditions in due course.
This is a multidisciplinary project involving synthetic organic and inorganic chemistry, enzymology and glycobiology. The proposal centres on the development of expedient synthetic and chemo-enzymatic methodologies for the preparation of novel multivalent O-glycan probes that will be used in the screening of O-glycosylation-linked interactions in health and in disease. These studies will help us understand the parameters controlling the combinatorial diversity of O-glycans and the implications of such diversity on receptor binding and subsequent intracellular signalling, which in turn will lead us to the development of new glycan-based diagnostic tools and therapeutics.
Campo scientifico
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP.
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP.
- natural sciencesbiological sciencescell biologycell signaling
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- natural sciencesbiological sciencesbiochemistrybiomoleculescarbohydrates
- natural scienceschemical sciencesinorganic chemistry
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
BS8 1QU Bristol
Regno Unito